1. Field of the Invention
The present invention relates to novel disulfide derivatives useful for treating allergic diseases.
2. Description of the Related Art
Antihistamines and mast cell stabilizers are two types of drugs currently used topically to treat allergic diseases. Antihistamine drugs are used to interrupt the allergic effects that histamine causes after it has been released from a mast cell. Many topical antihistamine drugs are marketed. For example, emedastine difumarate and levocabastine hydrochloride are available for ocular allergies (see Ophthalmic Drug Facts 1999, Facts and Comparisons, St. Louis, Mo., pp. 59-80).
Mast cell stabilizers prevent mast cells from xe2x80x9cdegranulatingxe2x80x9d or releasing histamine and other components or xe2x80x9cmediatorsxe2x80x9d during an allergic reaction. Examples of ophthalmic drugs marketed as mast cell stabilizers include olopatadine (see U.S. Pat. No. 5,641,805) and cromolyn sodium.
U.S. Pat. No. 4,705,805 discloses certain disulfide derivatives that are useful as anti-thrombotic agents. The disulfide derivatives suppress blood platelet aggregation. The ""705 patent does not disclose the use of disulfide derivatives in the topical treatment of allergic diseases of the eye or nose.
The present invention provides methods for preventing or treating allergic diseases of the eye, nose, skin, ear, gastrointestinal tract, airways or lung. The methods may also be used to treat manifestations of systemic mastocytosis. The methods of the present invention comprise topically or systemically administering to a patient a novel mast cell stabilizing disulfide derivative of the formula 
wherein
X=xe2x80x94NHC(=O)NHxe2x80x94R;
R=H; (un)substituted phenyl; (un)substituted benzyl; or C1-C8 alkyl or alkenyl, optionally substituted with or terminated by OH, OR2, NR3R4; C4-C7 cycloalkyl, (un)substituted aryl, or (un)substituted 5-7 membered heterocyclic ring; where optional substituents are selected from the group consisting of C1-C6 alkyl or alkoxy; halogen; OH; CN; CF3; NO2; and CO2R2;
R2=C1-C3 alkyl; and
R3 and R4 are independently H; benzyl; C1-C8 alkyl or alkenyl; C4-C7 cycloalkyl; (un)substituted aryl; or (un)substituted 5-7 membered heterocyclic ring; wherein optional substituents are selected from the group consisting of C1-C6 alkyl or alkoxy; halogen; OH; CN; CF3; NO2; and CO2R2.
The present invention is also directed toward topically or systemically administrable compositions for treating or preventing allergic diseases of the eye, nose, skin, ear, gastrointestinal tract, airways or lung and treating or preventing manifestations of systemic mastocytosis, wherein the compositions comprise a disulfide derivative of formula (I).
The disulfide derivatives of formula (I) can be made as described in Scheme 1. 
The appropriate isocyanate is added to a stirring solution of the bis amino-disulfide in a solvent such as tetrahydrofuran or methylene chloride at a temperature between xe2x88x9220xc2x0 C. and 30xc2x0 C. An organic base such as triethylamine, or pyridine is added after the reaction mixture has stirred for 5 to 30 minutes and the reaction is stirred for 6 to 48 hr. The disulfides can then be isolated using standard, known procedures.
Preferred compounds of formula (I) are those having the X substituents in the ortho position and wherein R=C1-C8 alkyl or alkenyl, optionally substituted with or terminated by OH, OR2, NR3R4; C4-C7 cycloalkyl, (un)substituted aryl, or (un)substituted 5-7 membered heterocyclic ring; where optional substituents are selected from the group consisting of C1-C6 alkyl or alkoxy; halogen; OH; CN; CF3; NO2; and CO2R2. Most preferred are compounds wherein R=C1-C5 alkyl or alkenyl, optionally substituted with or terminated by OH, OR2, NR3R4; C4-C7 cycloalkyl, (un)substituted aryl, or (un)substituted 5-7 membered heterocyclic ring; where optional substituents are selected from the group consisting of C1-C6 alkyl or alkoxy; halogen; OH; CN; CF3; NO2; and CO2R2.
Compounds of formula (I) may be administered topically (i.e., local, organ-specific delivery) or systemically by means of conventional topical or systemic formulations, such as solutions, suspensions or gels for the eye and ear; nasal sprays or mists for the nose; metered dose inhalers for the lung; solutions, gels, creams or lotions for the skin; oral dosage forms including tablets or syrups for the gastrointestinal tract; and parenteral dosage forms including injectable formulations. The concentration of the compound of formula (I) in the formulations of the present invention will depend on the selected route of administration and dosage form. The concentration of the compound of formula (I) in topically administrable formulations will generally be about 0.00001 to 5 wt. %. For systemically administrable dosage forms, the concentration of the compound of formula (I) will generally range from about 10 mg to 1000 mg.
The preferred formulation for topical ophthalmic administration is a solution intended to be administered as eye drops. For solutions intended for topical administration to the eye, the concentration of the compound of formula (I) is preferably 0.0001 to 0.2 wt. %, and most preferably from about 0.0001 to 0.01 wt. %. The topical compositions of the present invention are prepared according to conventional techniques and contain conventional excipients in addition to one or more compounds of formula (I). A general method of preparing eye drop compositions is described below:
One or more compounds of formula (I) and a tonicity-adjusting agent are added to sterilized purified water and if desired or required, one or more excipients. The tonicity-adjusting agent is present in an amount sufficient to cause the final composition to have an ophthalmically acceptable osmolality (generally about 150-450 mOsm, preferably 250-350 mOsm).
Conventional excipients include preservatives, buffering agents, chelating agents or stabilizers, viscosity-enhancing agents and others. The chosen ingredients are mixed until homogeneous. After the solution is mixed, pH is adjusted (typically with NaOH or HCl) to be within a range suitable for topical ophthalmic use, preferably within the range of 4.5 to 8.
Many ophthalmically acceptable excipients are known, including, for example, sodium chloride, mannitol, glycerin or the like as a tonicity-adjusting agent; benzalkonium chloride, polyquaternium-1 or the like as a preservative; sodium hydrogenphosphate, sodium dihydrogenphosphate, boric acid or the like as a buffering agent; edetate disodium or the like as a chelating agent or stabilizer; polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylic acid, polysaccharide or the like as a viscosity-enhancing agent; and sodium hydroxide, hydrochloric acid or the like as a pH controller.
If required or desired, other drugs can be combined with the disulfide derivatives of formula (I), including, but not limited to, antihistaminic agents, anti-inflammatory agents (steroidal and non-steroidal), and decongestants. Suitable antihistaminic agents include emedastine, mapinastine, epinastine, levocabastine, loratadine, desloratadine, ketotifen, azelastine, cetirazine, and fexofenadine. The preferred antihistaminic agent for ophthalmic use is emedastine, which is generally included in topically administrable compositions at a concentration of 0.001-0.1 wt. %, preferably 0.05 wt. %. Suitable anti-inflammatory agents includemometasone, fluticasone, dexamethasone, prednisolone, hydrocortisone, rimexolone and loteprednol. Suitable decongestants include oxymetazoline, naphazoline, tetrahydrozoline, xylometazoline, propylhexedrine, ethylnorepinephrine, pseudoephedrine, and phenylpropanolamine.
According to the present invention, the disulfide derivatives of formula (I) are useful for preventing and treating ophthalmic allergic disorders, including allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis; nasal allergic disorders, including allergic rhinitis and sinusitis; otic allergic disorders, including eustachian tube itching; allergic disorders of the upper and lower airways, including intrinsic and extrinsic asthma; allergic disorders of the skin, including dermatitis, eczema and urticaria; allergic disorders of the gastrointestinal tract, including systemic anaphylaxis resulting from ingestion of allergen and iatrogenic anaphylaxis caused by contrast agents used during diagnostic imaging procedures; and manifestations of systemic mastocytosis including hypotension.